A high incidence of oral cancer is associated with aging. This project's long-term objectives are to develop better prevention and treatment strategies for oral cancer. We hope to accomplish this objective by modulating antioxidant enzymes (copper and zinc-containing superoxide dismutase [Cu-ZnSOD], manganese-containing superoxide dismutase [MnSOD], catalase [CAT], and glutathione peroxidase [GPX]) in cells. This proposal is intended to examine the role of the antioxidant enzymes and, in particular, MnSOD, in oral cancer. To our knowledge, there has been no work performed to date on these enzymes in oral tissues. Thus, we first propose to determine using the techniques of immunohistochemistry if the levels of any of the antioxidant enzymes change during chemical carcinogenesis in the hamster cheek pouch model. The reason(s) for any changes in these enzymes in both hamster and human oral tumors will then be determined at the molecular level; this will be accomplished using enzyme activity assays, Western, Northern, and Southern blotting. Last, the effects of transfecting sense and antisense MnSOD cDNA into cultured oral tumor cell lines on sensitivity to oxidative stress and on the malignant phenotype will be studied. Oxidative stress sensitivity will be determined by measuring survival after exposure to four antitumor agents (adriamycin, bleomycin, tumor necrosis factor and ionizing radiation). The malignant phenotype will be measured both in vitro (by tests such as growth in soft agar) and in vivo (by injecting cells into nude mice or syngeneic animals). Our studies will help to determine the mechanism of oral carcinogenesis and thus may suggest which antioxidants may be of particular value in preventing this cancer. Oral cancer remains a treatment problem. Information on modulation of MnSOD activity will tell us whether such manipulation could be of use in cancer therapy to eliminate tumor drug resistance or to protect normal tissue. Moreover, increasing MnSOD might be used for differentiation therapy of oral tumors, since our recent work suggests that such an approach could be useful in treating human melanoma. Thus, this proposal has relevance to both cytotoxic and differentiation therapy of cancer.